The major objectives of this proposal are to elucidate the mechanism(s) responsible for tolerance development of barbiturates, especially phenobarbital (PB) in the central nervous system (CNS) and its relationship to the hepatic metabolism of this class of agents. To obviate the contribution of the liver, we have developed a rat model in which tolerance to PB is produced by chronic intracerebroventricular (i.c.v.) adminstration of th drug. Recently, we have found that chronic central injection of PB into hypophysectiomized or adrenalectomized rats results in hypersensitivity to the hynotic effects of the drug rather than tolerance. Both these phenomena will be examined by investigating the turnover of Acetylcholine and Serotonin in various brain regions, by analyzing for alterations in synaptic membrane proteins, and by determining the effect of pituitary-adrenal hormones on the development and maintenance of either tolerance or hypersensitivity.